Oxypurin and process of making same.



my invention, is styled fi-oxy-purin under the UNITED STATES PATENT OFFICE EMIL FISCHER, OF BERLIN, GERMANY, ASSIGNOR TO C. F. BOEHRINGER &

SOEHNE, OF WALDHOF, GERMANY.

OXYPURIN AND PROCESS OF MAKING SAME.

,LS PEGIFIGATION forming part of Letters Patent N 0. 631,709, dated August 22, 1899. Application filed January 31, 1898. Serial No. 668,647. Specimens) To (all whom it may concern.-

Be it known that I, EMIL FISCHER, a citizen of the Empire of Germany, residing at Berlin, in the Empire of Germany, have invented certain new and useful Improvements in the Manufacture of Oxypurins and their Derivatives; and I do hereby declare the following to be a full, clear, and exact description of the invention, such as will enable others skilled in the art to which it appertains to make and use the same.

The present invention relates to the preparation of oxy-purins and their alkyl derivatives, and particularly the production of a series of bodies starting from trich1oropurin,

a compound which is described in Letters Patent of the United States No. 598,502, dated February 8, 1898.

The present invention has for its specific object the preparation of hypoxanthin and involves also the preparation of the intermediate new body 6-oxy-2-8-dichloropurin,which is a derivative of trichloropurin.

Before proceeding with the description it should be stated that the nomenclature here- ,in followed is that adopted by the article published in Bem'chte der Deutschen Chemz'schen Gesellschaft, Vol. 30, page 549. According to this nomenclature a large number of bodies, such as cafiein, uric acid, guanin adenin, &c., are designated by the generic term purins and their nucleus. The purin group has its several carbon and nitrogen atoms num bered in the following manner:

Bearing this nomenclature and system of numbering the position of the atoms in mind the use of terms in the following description will be readily understood. Thus, for example, the compound hypoxanthin, which may be obtained synthetically by the application of new nomenclature, since it has the structural formula: I

For the purpose of outlining my invention I will state that when acting upon trichloropurin with alcoholic alkali at ordinary roomtemperature the former is converted into 6- ethoxy-Z-S-dichloropurin or 6-methoxy-2-S- dichloropurin (according as ethyl or methyl alcohol is used) having the formula:

N:C.O.O2H5 N=0.o.0u

01.0 ONH or 01.0 'ONH 0.01 1 001 11 n-o-n N-O-N When either of the latter is heated with hydrochloric acid, it loses the ethyl or methyl group, giving rise to 6-oxy-2-8-dichloropurin having the formula:

HNOO

010 O-NH ALA-r2 the latter being in turn by reducing agents converted into 6-ox'ypurin:

IIN-CO HO C-NH ll II which has been shown to be identical with natural hypoxanthin. This splitting ofi of ethyl and the substitution of hydrogen for the ehlorin atoms may also be accomplished directly in one operation by treating the 6- ethoxy-2-8-dichloropurin with hydriodic acid, in which case hypoxanthin is also obtained.

The intermediate compound 6-oxy-2-8-dichlopreparing hypoxanthin from a 2-S-dichloro-6- oxy-purin having an alkyl radical combined with the oxygen or from the same.

My invention also comprises such other feai tures and methods as will be hereinafter set' forth and pointed out in the claims.

The 2-8-dichloro-G-alkyl-oxy-purin, which constitutes a link in thechain of manufacture of hypoxanthin under one modification of my invention, while herein described to f nlly disclose my invention, is not herein claimed,

however, being the subject-matter of my application, Serial No. 668,648, filed concur-' rently herewith, nor is the specific method of its manufacture herein covered by claim,2

part of the said concur- I Q. Preparation of In the following detailed description I wil first describe the preparation of 6-oxy-2-8- dichloropurin by proceeding either from the dichloro-alkyl-oxypurin or from trichloropurin and then the preparation of the hyposince that also is a rent application.

xanthin from a dichloro-oxypurin without or with analkyl the position 6.

rin.

in myaforesaid patent, N 0. 598,502, dissolved 3 group bound to the oxygen in f in sixteen parts of alcohol, and this solution;

after being rapidly cooled to about 10 to 15 i centigrade, and which, as a rule, has a tend-j, ency to throw out crystals of the trichloro-5 purin, is added to a solution of one and twotenths parts of sodium in twenty-four parts of alcohol cooled to room-temperature. A? clear pale-yellow liquid results, which is spontaneously heated to about 30 centigrade,i

and soon becomes turbid by reason of a pre-;

cipitation of sodium-chlorid.

for three hours, whereupon fifty parts of wa-;

The mixture; is allowed to stand at ordinary temperature ter are added and the whole is supersaturated slightly with acetic acid. The alcohol is then evaporated off, whereby the dichloro-ethoxy-; :purin is precipitated in colorless very flexible P aeicu-lar crystals. The sameis then purified haloid acid. best manner-to carry out this process: lmix by recrystallization from hot benzene. Its formula is C H CI N O or but dissolves readily in hot alcohol and aceton.

The above converting process proceeds according to the equation:

N: 0. Cl

01.0 O NH nzeoo ir,

2 8 Dichloro-(i-Methomy- Pit-rin.

If in the place of the e'thyl-aleoholic'solw 'tion a methyl-alcoholicsolution of sodium is employed, the other ingredients and conditions of the above process remaining thesame, I obtain 2-8-dich-loro-fi methoxy-pur'in, which melts and decomposes at about 225 centi- 1 grade and which is considerably less soluble 1. Preparation of 2-,8-Dichl0r0-G-Ethowy-Pain benzene than the ethoxy compound.

The generic formula for both of the oxy- 5 al'kyl-d-iehl'oro-purins is:

N=0.0.Alk.

ore -C-NI-I o 1 H i NO-N 3. Preparation of G-Oacy-Z- S-DichZoro-Parin.

Process a.The 2-8-dichloro-6-ethoxy-purin described under example 1 may be converted into the new compound 6-oxy-2-8-di-.

chloro-purin by a mineral acid, preferably a 1 find the following to be the powdered 2-8-dichloro-6 ethoxypurin with five times its weight of fuming hydrochloric acid and heat the mixtureon the water-bath. Solution rapidly takes place, and the difiicu-ltly-soluble 6-oxy-2-8-diehloro-purin is soon thrown out in the form of coarse crystals.

' The conversion will be completed in about a half-hour, after which the whole is diluted with about ten parts of water and allowed to cool, after which the mother-liquor is separated from the crystals by filtration.

For the purpose of complete purification the new body is converted into the potassium salt, which is completely decolorized by recrystallization from hot water, to which some animal charcoal is added. The oxy-dichloropurin when recovered from the potassium salt forms beautifu l colorless'acicular crystals having the formula C N H Cl O or I-IN-CO 01.0 o-nn 001 ll// N-CN Process b.The 6-oxy-2-8-dichloro purin may be obtained directly from the trichloropurin by substituting aqueous for alcoholic alkali in example 1 and heating the mixture. The chlorin atom is in this manner readily replaced by the hydroxyl group. The following detailed description discloses what I consider the preferred method of carrying out this modification. An amount of trichloropurin is dissolved in sufficient potash lye to make the amount of alkali correspond to three molecules. The liquid is then heated to 100 centigrade and maintained at this temperature for three hours. The same thus acquires a pale-pink color.

The solution is then supersaturated with hydrochloric acid,

whereby the 6-oxy-2-8-dichloropurin is thrown out in the form of fine reddish acicular crystals. The further purification is carried out in the manner set forth under Process a.

The above process is explained in the following equation:

4. Preparation of Hypoxanihins.

(a.) Preparation of hypoxanthinfrom 6-00cy 2-8-d-iohZo1'o-paria.-One part of the finelypowdered oxydichloropurin is added to ten parts hydrogen iodid or hydriodic acid of the specific gravity 1.96 and after about one-half part of phosphonium iodid or yellow phosphorus has been added the whole is first shaken for about an hour at ordinary temperature and then heated on the water-bath until an almost colorless solution is formed. On cooling the hydro-iodate of hypoxanthin is thrown out in the form of beautiful crystals. The entire quantity of this product is obtained by evaporating the hydrogen iodid. The reaction takes place according to the equation:

-After forming a concentrated aqueous solution of the hydro-iodate, the hypoxanthin may be obtained therefrom by neutralizing with ammonia. The product thus obtained is purified by recrystallizing from hot water, animal charcoal being added. The artificial compound thus prepared unites all the properties of natural hypoxanthin or 6-oxy-purin.

(1).) Preparation of hypowantht'n from 2-8- clt'chloro-6-ethoazyparin.If in place of the simple oxy dichloropurin, we employ the ethylized product, the 2-8-dichloro-6-ethoxytwo chlorin atoms,but also the ethyl radical-r that is to say, hypoxanthin or (i-oxy-purin will again result.

What I claim, and desire to secure by Letters Patent of the United States, is

1. The process which consists in treating a 2-8-dichloro-6-alkyl-oxy-purin with a mineral acid to remove the alkyl group.

2. The process which consists in mixing 2-8-dichloro-fi-ethoxy-purin with fuming hydrochloric acid and heating the mixture.

3. The process which consists in mixing 2-8-dichloro-6-eth0Xy-purin with fuming 113 drochloric acid and heating the mixture, then diluting with water and allowing to cool, then filtering and converting the residue into the potassium salt, recrystallizing from hot water with animal charcoal and recovering the oxydichloropurin.

4. As a new chemical compound, 6-oxy-{ 2-S-dichloro-purin which has the formula above given, which is soluble only With diffir' culty in water, but more soluble in alcohol; whose aqueous solution has an acid reaction, which decomposes and turns brown when heated to over 350, centigrade, and which: may be obtained in the form of colorless crystals. 5. The process of preparing hypoxanthin which consists in submittingaQ-S-diohloro-G- oxy-purin to areducing agent.

6. lhe process of preparing hypoxanthin which consists in submitting 2-8-dichloro-6- oxy purin to the action of hydriodic acid and phosphonium iodid. a

7. The process which consists in adding 6-oxy-2-8-dichloropurin to hydriodic acid and phosphonium iodid, shaking the whole at ordinary temperature and then heating and then cooling and filtering the crystals of hydro-iodate of hypoxanthin, dissolving the same in waterand neutralizing with ammonia to thus obtain free hypox'anthin;

8. The process which consists in converting 2-S-dichloro-G-alkyl-oxy-purin into a di chloro-oXy-purin free from alkyl, by treating the former with hydrochloric acid and then submitting the resultant product to a reducing agent.

9. The process which consists in treating 2-8-dichloro-6-alkyl oxy purin with hydro- 1 chloric acid and then submitting the result ant 2-S-dichloro-6-oxy purin to hydrogen iodid and phosphonium iodid, all substantially as set forth.

In testimony whereof I afiix my signature in presence of two witnesses.

EMIL FISCHER.

Vitnesses:

CHAS. H. DAY, HENRY IIASPER. 

